2- and 4-[18F]fluorotropapride, two specific D2 receptor ligands for positron emission tomography: N.C.A. syntheses and animal studies

Tropapride, (exo)-2,3-dimethoxy-N-[8-(phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]benzamide hydrochloride, has been labeled with fluorine-18 at the 2- and 4-positions of its benzylic group. Two synthetic pathways were investigated: the first one required the alkylation of the norbenzyl precursor with 2- or 4-[¹⁸F]fluorobenzyl bromide (radiochemical yield of 5% EOB, 180 min); the second method consisted of a reductive amination of norbenzyl tropapride with 2- or 4-[¹⁸F]fluorobenzaldehyde (20% EOB, 110 min). In both cases, the specific activity was found to be greater than 1 Ci/μmol (EOS). Animal studies in rats showed the percentage of the injected dose localizing in the whole brain to be 0.6 ± 0.09 and 0.2 ± 0.03 at 2 h post injection for the para- and the ortho-[¹⁸F]fluoro analogs of tropapride respectively. Cerebral biodistribution studies showed at 4 h a striatum uptake of 5 ± 0.7% of the injected dose per gram of striatum for the para derivative with a low fixation into the frontal cortex and the cerebellum (% ID/gFC < 0.4 and % ID/gCb < 0.3). The selectivity of 4-[¹⁸F]fluorotropapride for D₂ dopaminergic sites was demonstrated through blocking experiments with ketanserin, spiperone and halopemide. The saturability was confirmed by the use of variable specific activities. These preliminary results showed that 4-[¹⁸F]fluorotropapride can be considered as a potent radiopharmaceutical for the study of the dopaminergic system with PET.